1. Field of the Invention
The present invention is directed to a vaginal pharmaceutical composition which is in gel form and particularly to a composition which is able to maintain or enhance the normal protective function of the vaginal flora. More particularly, it relates to a vaginal composition useful for the prevention, treatment, mitigation, diagnosis and cure of diseases and the prevention of conception.
2. Description of the Prior Art
One of the main disciplines of medicine is the treatment of the female reproductive system for the prevention, treatment, mitigation, diagnosis and cure of diseases, and the prevention of conception. Usually, this involves the delivery of active agents to the vaginal cavity and its environs. Systems to effect the delivery of such agents are usually in the form of gels, foams, creams, suppositories and quick dissolving tablets.
The vaginal cavity is subject to conditions which render it a target for disease and infection; however, it is extremely difficult to deliver an active agent to this area for an extended period of time. The vaginal cavity exhibits an aqueous environment containing secreting glands whose fluids create an acidic pH in the range of 4.0 to 5.5. The environment of the vagina is conducive to the growth of bacteria, fungi, yeast and other microorganisms since it warm, moist and dark. It is also the vestibule for menstrual debris and residual seminal fluid from sexual intercourse. The crevices of the vaginal cavity facilitate the retention of undesirable bacteria, fungi, yeast and other microorganisms, as well as the debris from menstruation and sexual intercourse. The vaginal cavity is also subject to considerable physical deformation, such as during sexual intercourse or during the insertion of tampons.
Infectious diseases and other inflammatory conditions affecting the vaginal mucosa and often secondarily involving the vulva are commonly referred to as vulvovaginitis. Physicians and investigators often believe that the normal vaginal flora has a role in protecting the vagina and contiguous tissues from various microorganisms that are causes of vulvovaginitis.
Most vulvovaginitis and symptomatic vaginal discharges are caused by bacteria, usually Gardnerella vaginalis in combination with various anaerobes. Protozoa (Trichomonas vaginalis) cause one-third of all cases. Candida is a frequent cause in pregnant women and diabetics, and occasionally oral contraceptives increase susceptibility. Candida also causes symptoms in women who do not have the risk factors of diabetes, pregnancy, and hormonal therapy.
Another major cause is the human papillomavirus (HPV) The lesions from HPV are usually not described as vulvovaginitis although they do cause vulvovaginal infection. The condition is not inflammatory (vaginitis) but rather wart-like outgrowths of the tissue of the vagina, vulva and cervix and usually do not elicit any symptoms of pain or itching. But most importantly HPV is probably the most significant cause of cervical cancer in women.
Other less common causes of vulvovaginitis are other bacteria (e.g., Neisseria gonorrhoeae, members of the Chlamydia and Mycoplasma groups, streptococci, Escherichia coli, and staphylococci), foreign bodies, viral infections (herpes simplex and HIV infections), pinworms (Enterobius vermicularis), fistulas, radiation, and tumors of the genital tract. Frequent douching, especially with chemicals, may disturb normal vaginal milieu. Deodorant sprays, laundry soaps and fabric softeners, and bath water additives may cause vulvar irritation. Tight, nonporous, nonabsorbent underclothing, as well as poor hygiene, may foster fungal and bacterial growth. Occasionally, sensitivity to spermicides, coital lubricants, or latex in a diaphragm or condom causes irritation.
Active agents which have pharmaceutical qualities have been developed and approved for use in the treatment of afflictions of the vaginal cavity and the prevention of conception. These include fungicides, spermicides, etc. Although pharmaceutically active agents have been developed, it has been difficult to achieve optimal potential effectiveness from these agents. It has been found that gels, foams, creams, suppositories and tablets that are presently used as vaginal delivery systems break down almost immediately following insertion into the vaginal cavity and have minimal bioadherence to the vaginal walls. This is believed to be due to their water miscibility and/or their lack of physical stability at 37 degrees C. (body temperature). Thus, they exhibit limited effectiveness.
In this regard, some of the more conventional treatment regimens for various vaginal diseases have been described as follows: Candida is treated topically with miconazole 2% or clotrimazole 1% cream, vaginal tablets, or suppositories for three to seven days. Trichomonas is treated with metronidazole 250 mg tid or 500 mg bid orally for five days; 2 gm in a single daily dose may be used. Ideally, the sexual partner should also be treated. Gardnerella or anaerobic infections are treated similarly to Trichomonas, with metronidazole. About 25% of patients have recurrences and require re-treatment in two to three months. Lowering vaginal pH with propionic acid jelly has also been suggested. Chlamydial infections are treated with doxycycline 100 mg bid or erythromycin 500 mg qid orally for seven days. Mycoplasma is treated with doxycycline 100 mg bid orally for ten days. For any of these infections, sexual partners should be treated simultaneously, if possible.
Conventional treatments thus have two important negative characteristics. Some of the treatments described are systemic, such as oral metronidazole for trichomonas or bacterial vaginosis and tetracycline for chlamydia. Systemic treatment may have systemic side effects. The second difficulty is that while some treatments are listed that are available, for some infectious agents, such as HIV, there is no treatment or preventive product available. This is a serious deficiency in current therapy. Also, Herpes infections are treated with oral, injectable or topical acyclovir which is a nucleoside analog and may induce some unwanted side effects and precautions include issues of carcinogenesis, mutagenesis and impaired fertility.
Furthermore, none of these treatments or procedures, however, attempt to normalize the vaginal flora growth habitat by either maintaining or enhancing acceptable microbial growth patterns.
The present invention is advantageous in that it provides a system for the delivery of an active agent in a controlled manner in the vaginal cavity for an extended period of at least three hours. The system may be used to treat a particular disease state or condition as well as be used on a routine basis to maintain normal vaginal floral activity. This system takes the form of a gel which is easily introduced into the vaginal cavity but does not seep from this body cavity in an offensive manner. It is further advantageous since it reduces the treatment period for active agents including antifungals, such as, imidazoles. It also possesses antimicrobial activity against a variety of microorganisms responsible for sexually transmitted infections and vaginitis acting through direct antimicrobial action and by maintaining and enhancing the normal protective function of the vaginal flora.